- Email: [email protected]
Clinical and Post Approval Safety Data Management
CHAPTER
CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
27 Rajinder K. Jalali
Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India
A medicinal product goes through preclinical, clinical, and post approval safety surveillance throughout its lifecycle. Before testing a new medicine in humans, various in vitro, in vivo, and toxicological studies are conducted to understand the effects of medicinal products in animals. This forms the basis of potential risk expected in humans, which is further investigated in various phases of clinical trials before a medicine is granted permission to be marketed. The limitations of testing safety in humans in clinical trials is fraught with small size of patient population studied, narrow populations tested, insufficient data on special population groups, and short duration of these studies. On the other side, benefits of post marketing monitoring is the ability to identify rare adverse effects, adverse effects in special population groups, long term effects and effects of interaction with other drugs. Further, it is important to understand that a medicinal product will be under various stages of development and/or marketing in different countries at some point in time. Both clinical safety and post approval safety data need to be processed in the company’s safety database and reported to various regulatory agencies as per regulatory requirements in various countries [1,2]. Definitions and terminology [1 4] used in clinical and post approval safety reporting are in general as follows: 1. Adverse Event (AE) An adverse event is any untoward medical occurrence (unfavorable or unintended sign including an abnormal laboratory finding, symptom or disease) temporally associated with the use of a medicinal product administered to a clinical investigation subject or patient and which does not necessarily have a causal relationship with the medicinal product. 2. Adverse Drug Reaction (ADR) a. During clinical phase, all noxious and unintended responses to a medicinal product related to any dose are considered ADRs. b. During post approval phase, ADR is a response to a drug which is noxious and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or treatment of disease or modification of physiologic function. 3. Unexpected Adverse Drug Reaction An adverse reaction, the nature, severity, specificity or outcome of which is not consistent with the applicable product information (Investigator Brochure during clinical safety reporting and Prescribing Information/Summary of Product Characteristics during post approval safety Pharmaceutical Medicine and Translational Clinical Research. DOI: http://dx.doi.org/10.1016/B978-0-12-802103-3.00028-6 © 2018 Elsevier Inc. All rights reserved.
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reporting). This includes class-related reactions, which are mentioned in the regulatory authority approved product information but which are not specifically described as occurring with the product. 4. Serious adverse Event or Adverse Drug Reaction Serious adverse event is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny marketing authorization for a drug. A serious adverse event or serious adverse drug reaction is any untoward medical occurrence at any dose and results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/birth defect or is a medically important event or reaction. Other Important Medical Events have also been listed in European Medicine Agency release and are considered serious in post approval safety reporting for adverse events. 5. Expectedness of an Adverse Drug Reaction The following documents are used to determine whether an adverse event/reaction is expected: For a medicinal product not yet approved for marketing in a country, a company’s Investigator Brochure is used as a source document. During postapproval phase Prescribing Information or Summary of Product Characteristic is used as a source document. a. Reports which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events. Some of the examples are (1) acute renal failure as a labeled ADR with a subsequent report of interstitial nephritis, (2) hepatitis with subsequent report of hepatic necrosis, and (3) cerebral thrombosis with first report of cerebral vascular accident. During clinical trial phase, clinical trial or epidemiological investigation is the source of ICSRs and during post approval phase, it is divided into unsolicited or solicited sources [1 7]. 1. Unsolicited Source a. Spontaneous Reports A spontaneous report is an unsolicited report by a healthcare professional (medically qualified person such as physician, dentist, pharmacist, nurse) or consumer (patient, friend, relative, or lawyer of a patient) to a pharmaceutical company, Regulatory Agency, or other organization such as World Health Organization or a Regional ADR Monitoring Centre, that describes one or more adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a clinical study or any organized data collection scheme. Other forms of spontaneous reports are stimulated reports. Stimulated reports are those that may have been motivated, prompted, or induced such as “Dear Doctor letter,” public advisory issued by regulatory agencies, media reports, or questioning of healthcare professional by company representatives. b. Literature Each Marketing Authorization Holder (MAH) is expected to undertake global literature monitoring by accessing widely used systematic literature reviews or reference databases such as PubMed or Embase or outsourcing literature monitoring activity to an outside contract organization. The frequency of literature searches depends upon any local regulatory requirements or should be done at least weekly. Cases of ADRs from the
CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
409
scientific and medical literature, including relevant published abstracts from conferences and draft manuscripts from meetings, might qualify for expedited reporting. A copy of the article/abstract is required to accompany the report. The regulatory reporting time clock starts as soon as the MAH, its Affiliates, or outsourced contract organization has knowledge that the case meets minimum criteria for reporting. If the product source, brand or trade name, or batch number is not specified, the MAH should assume that it was its product. If a number of products have been mentioned in the article, a report should be submitted only by the MAH whose product is considered as a suspect by the author of the article. c. Websites MAH should regularly screen websites under its management for any potential ADR case reports. MAH is not expected to screen external websites for ADR information. However, if MAH becomes aware of ADR from such external websites, the MAH should assess whether the report needs to be sent to regulatory authority. ADR data collection should be facilitated by pharmaceutical companies by providing ADR forms on company website. d. Other sources of unsolicited reports If MAH becomes aware of ADR from one of its products from press or other media, it should be handled as a spontaneous report. 2. Solicited Sources Reports derived from organized data collection systems are known as solicited reports. Examples include reports derived from clinical trials, patient registries, post approval patient programs, other patient support and disease management programs, surveys of patients or healthcare providers or information gathering on efficacy and patient compliance. Adverse event reports obtained from any of these sources are classified as study reports for safety reporting purpose, and should have an appropriate causality assessment by a healthcare professional (HCP) or an MAH. 3. Safety Data Exchange Agreements The marketing of many products takes place through contractual agreements between two or more companies, which may market the same product in the same or different regions/ countries. It is very important to have Safety Data Exchange Agreements in place defining the process for exchange of safety information, including timelines and regulatory reporting responsibilities. Processes should be in place to avoid duplicate reporting. 4. Regulatory Authority Sources Individual serious unexpected adverse drug reaction reports originating from foreign regulatory authorities are subject to expedited reporting to other authorities by each MAH. Such reports usually need not be sent to originating regulatory authority unless otherwise stated. An individual case safety report (ICSR) is considered to be valid if it meets at least four minimum criteria, i.e., it has: (1) an identifiable reporter, (2) an identifiable patient, (3) an adverse reaction, and (4) a suspect product. If one or more of these four criteria is missing, the case is not a valid AE report, i.e., reportable to a regulatory agency. However, if there is information regarding drug and adverse event, it needs to be databased, and the information may be used in assessment of risk-benefit balance and signal generation.
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CHAPTER 27 CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
All ADRs from clinical or epidemiological investigation, spontaneous reports, and reports from regulatory agencies or literature that are both serious and unexpected are subject to expedited reporting [5,6]. The source of report (investigation, spontaneous, other) should always be specified. Causality assessment is required for clinical trial cases. All cases judged by either clinical investigator or sponsor as having a reasonable suspected causal relationship to the investigational product are subjected to expedite reporting. For purposes of safety reporting, adverse event reports associated with marketed products (spontaneous reports) are considered to have implied causality. Serious adverse events from clinical trials which are not related to study medication are not subjected to expedite reporting. Reports which are serious but expected are not usually required to be expedited. However, expected serious ADRs showing significant increase in frequency will require to be processed on an expedite basis. Lack of efficacy for life-threatening disease, vaccines, or contraceptives are considered as expedited reports. Reports of overdose, dosing error with no adverse event outcome need not be reported as adverse reactions. In a blinded clinical study, when a serious adverse reaction is judged reportable on an expedited basis, it is recommended that the blind be broken only for that specific patient by the sponsor even if the investigator has not broken the blind. It is also recommended that the blind be maintained for those personnel involved in analysis and preparation of clinical trial reports. The blind can be broken independently by the pharmacovigilance team involved in processing and reporting of adverse events for MAH to the regulatory agencies. However, when a fatal or other serious outcome is the primary efficacy endpoint in a clinical investigation, the integrity of the clinical investigation may be compromised if the blind is broken. Under these circumstances, it may be appropriate to reach agreement with regulatory authorities in advance regarding serious events that would be treated as disease-related and not subject to routine expedited reporting. Serious adverse events associated with an active comparator should be reported by sponsor to the manufacturer of the active control or to appropriate regulatory agencies. Adverse events associated with placebo will usually not satisfy the criteria for an ADR and, therefore, for expedited reporting. For poststudy events, a causality and expectedness assessment is needed for a decision on whether or not expedited reporting is required. All information related to SAEs should be shared with other Investigators and Ethics Committees and Institutional Review Boards as per ICH GCP Guidelines. In addition to ICSRs, any safety information that could change the risk-benefit evaluation for the product should be communicated to regulatory authorities such as safety findings from an in vitro animal or epidemiological, preclinical, or clinical study that suggests a significant human risk, such as evidence of mutagenicity, teratogenicity, carcinogenicity, or lack of efficacy with a drug used in a life-threatening or other serious disease. Fatal or life-threatening, unexpected ADRs from clinical trials need to be reported to regulatory agencies no later than 7 calendar days from the day of knowledge by the sponsor followed by complete report with assessment within additional 8 calendar days. Other serious, unexpected ADRs need to be reported within 15 calendar days after first knowledge by sponsor/company. When additional medically relevant information is received for a previously reported case (called initial case), the reporting time clock is considered to begin again for submission of the follow-up report. In addition, a case initially classified as a nonexpedited report would qualify for expedited reporting
CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
411
upon receipt of follow-up information that suggests that the case should be re-classified from nonserious to serious. Cases of nonserious ADRs need not be reported on an expedited basis. These nonserious ADRs are included in periodic safety update reports. However, in the European Union and some African and Latin American countries these are reported within 90 calendar days. The following elements need to be considered while processing ICSRs: 1. Assessing Patient and Reporter Identifiability Patient and reporter identifiability is important in order to avoid case duplication and facilitate follow-up of appropriate cases. One or more of the following should automatically qualify a patient as identifiable: age (or age category, e.g., adolescent, adult, elderly), gender, initials, date of birth, name, patient identification number. Further, a case should have minimum four criteria for case reporting. 2. The Role of Narratives The objective of the narrative should be to summarize all relevant clinical and related information in a logical sequence. Normally it should be presented in the chronology of patient experience. The narrative should summarize all relevant clinical and related information, including patient demography, medical and concomitant disease history, concomitant and other treatment details, investigations performed, clinical course of disease, diagnosis and ADRs with their outcome. Any relevant autopsy or postmortem findings—if any—should be included in the narrative summary. In follow-up reports, new information should be clearly identified. 3. Clinical Case Evaluation The report should include the verbatim term as used by the reporter or an accurate translation of it. Additional information should be sought from HCP, if required. 4. Follow-up Information Follow-up information should be sought for incomplete cases and the priority should be as follows: (1) serious and unexpected, (2) serious and expected, and (3) nonserious and unexpected. Follow-up information can be obtained via a telephone call and/or site visit and/or written request preferably using a targeted questionnaire. For serious ADRs, it is important to continue follow-up and report new information until the outcome has been established or the condition is stabilized. The duration for follow up of such cases is a matter of judgment. 5. Pregnancy Exposure All cases of pregnancy exposure received from HCPs or consumers where the embryo/fetus could have been exposed to one of its medicinal products, should be appropriately followed up. Patient may become pregnant either during the treatment or after the completion of treatment with a medicinal product, and then all such cases of exposed pregnancy shall be monitored for an adverse outcome or adverse drug reaction in the mother, fetus, infant, or child. Reports of pregnancy exposure are considered serious if they are associated with serious ADRs and/or with abnormal pregnancy outcome. All pregnancy exposure cases reported spontaneously shall be followed up to obtain pregnancy exposure outcome. Reports of induced termination of pregnancy without information on congenital malformation, reports of pregnancy exposure without outcome data, or reports which have a normal outcome, are not required to be reported as individual case reports since there is no adverse drug reaction. These reports form part of periodic safety update reports. However, all cases of use of a medicinal product during
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CHAPTER 27 CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
pregnancy are required to be submitted as individual case reports on expedited basis if there is a risk management program for one or more products to which the embryo/fetus has been exposed. The CIOMS-I form has been widely accepted standard for expedited adverse event reporting. Med Watch is used for reporting to US FDA, if E2B submission through electronic gateway runs into any trouble or is not possible. The Medical Dictionary for Regulatory Activities (MedDRA) should be used for coding adverse events. WHO DDE should be used for coding noncompany products and ICH E2B/M2 guidelines should be followed for electronic reporting of ICSRs.
REFERENCES [1] ICH E 2A: Clinical Safety data Management Definitions and Standards for Expedited Reporting (CPMP/ ICH/377/95), June 1995, European Medicines Agency. [2] ICH E2D: Post Approval Safety Data Management Note for Guidance on Definitions and Standards for expedited Reporting (CPMP/ICH/3945/03), November 1993, European Medicines Agency. [3] The Uppsala monitoring system, WHO collaborating Centre for International Drug Monitoring World Health Organization; 2002, pp. 28 34. [4] World Health organization. Safety of medicines. A guide to detecting and reporting adverse drug reactions why health professionals need to take action. Geneva: World Health Organization; 2002. [5] Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines, Food and Drug Administration, March 2001 (draft). ,http://www.fda.gov/cder/ guidance/4153dft.pdf.. [6] Safety Reporting Requirements for Human Drug and Biological Products, Proposed Rule, Food and drug Administration, March 2003. [7] ,http://www.ema.europa.eu..
CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
27 Rajinder K. Jalali
Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India
A medicinal product goes through preclinical, clinical, and post approval safety surveillance throughout its lifecycle. Before testing a new medicine in humans, various in vitro, in vivo, and toxicological studies are conducted to understand the effects of medicinal products in animals. This forms the basis of potential risk expected in humans, which is further investigated in various phases of clinical trials before a medicine is granted permission to be marketed. The limitations of testing safety in humans in clinical trials is fraught with small size of patient population studied, narrow populations tested, insufficient data on special population groups, and short duration of these studies. On the other side, benefits of post marketing monitoring is the ability to identify rare adverse effects, adverse effects in special population groups, long term effects and effects of interaction with other drugs. Further, it is important to understand that a medicinal product will be under various stages of development and/or marketing in different countries at some point in time. Both clinical safety and post approval safety data need to be processed in the company’s safety database and reported to various regulatory agencies as per regulatory requirements in various countries [1,2]. Definitions and terminology [1 4] used in clinical and post approval safety reporting are in general as follows: 1. Adverse Event (AE) An adverse event is any untoward medical occurrence (unfavorable or unintended sign including an abnormal laboratory finding, symptom or disease) temporally associated with the use of a medicinal product administered to a clinical investigation subject or patient and which does not necessarily have a causal relationship with the medicinal product. 2. Adverse Drug Reaction (ADR) a. During clinical phase, all noxious and unintended responses to a medicinal product related to any dose are considered ADRs. b. During post approval phase, ADR is a response to a drug which is noxious and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or treatment of disease or modification of physiologic function. 3. Unexpected Adverse Drug Reaction An adverse reaction, the nature, severity, specificity or outcome of which is not consistent with the applicable product information (Investigator Brochure during clinical safety reporting and Prescribing Information/Summary of Product Characteristics during post approval safety Pharmaceutical Medicine and Translational Clinical Research. DOI: http://dx.doi.org/10.1016/B978-0-12-802103-3.00028-6 © 2018 Elsevier Inc. All rights reserved.
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CHAPTER 27 CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
reporting). This includes class-related reactions, which are mentioned in the regulatory authority approved product information but which are not specifically described as occurring with the product. 4. Serious adverse Event or Adverse Drug Reaction Serious adverse event is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny marketing authorization for a drug. A serious adverse event or serious adverse drug reaction is any untoward medical occurrence at any dose and results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/birth defect or is a medically important event or reaction. Other Important Medical Events have also been listed in European Medicine Agency release and are considered serious in post approval safety reporting for adverse events. 5. Expectedness of an Adverse Drug Reaction The following documents are used to determine whether an adverse event/reaction is expected: For a medicinal product not yet approved for marketing in a country, a company’s Investigator Brochure is used as a source document. During postapproval phase Prescribing Information or Summary of Product Characteristic is used as a source document. a. Reports which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events. Some of the examples are (1) acute renal failure as a labeled ADR with a subsequent report of interstitial nephritis, (2) hepatitis with subsequent report of hepatic necrosis, and (3) cerebral thrombosis with first report of cerebral vascular accident. During clinical trial phase, clinical trial or epidemiological investigation is the source of ICSRs and during post approval phase, it is divided into unsolicited or solicited sources [1 7]. 1. Unsolicited Source a. Spontaneous Reports A spontaneous report is an unsolicited report by a healthcare professional (medically qualified person such as physician, dentist, pharmacist, nurse) or consumer (patient, friend, relative, or lawyer of a patient) to a pharmaceutical company, Regulatory Agency, or other organization such as World Health Organization or a Regional ADR Monitoring Centre, that describes one or more adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a clinical study or any organized data collection scheme. Other forms of spontaneous reports are stimulated reports. Stimulated reports are those that may have been motivated, prompted, or induced such as “Dear Doctor letter,” public advisory issued by regulatory agencies, media reports, or questioning of healthcare professional by company representatives. b. Literature Each Marketing Authorization Holder (MAH) is expected to undertake global literature monitoring by accessing widely used systematic literature reviews or reference databases such as PubMed or Embase or outsourcing literature monitoring activity to an outside contract organization. The frequency of literature searches depends upon any local regulatory requirements or should be done at least weekly. Cases of ADRs from the
CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
409
scientific and medical literature, including relevant published abstracts from conferences and draft manuscripts from meetings, might qualify for expedited reporting. A copy of the article/abstract is required to accompany the report. The regulatory reporting time clock starts as soon as the MAH, its Affiliates, or outsourced contract organization has knowledge that the case meets minimum criteria for reporting. If the product source, brand or trade name, or batch number is not specified, the MAH should assume that it was its product. If a number of products have been mentioned in the article, a report should be submitted only by the MAH whose product is considered as a suspect by the author of the article. c. Websites MAH should regularly screen websites under its management for any potential ADR case reports. MAH is not expected to screen external websites for ADR information. However, if MAH becomes aware of ADR from such external websites, the MAH should assess whether the report needs to be sent to regulatory authority. ADR data collection should be facilitated by pharmaceutical companies by providing ADR forms on company website. d. Other sources of unsolicited reports If MAH becomes aware of ADR from one of its products from press or other media, it should be handled as a spontaneous report. 2. Solicited Sources Reports derived from organized data collection systems are known as solicited reports. Examples include reports derived from clinical trials, patient registries, post approval patient programs, other patient support and disease management programs, surveys of patients or healthcare providers or information gathering on efficacy and patient compliance. Adverse event reports obtained from any of these sources are classified as study reports for safety reporting purpose, and should have an appropriate causality assessment by a healthcare professional (HCP) or an MAH. 3. Safety Data Exchange Agreements The marketing of many products takes place through contractual agreements between two or more companies, which may market the same product in the same or different regions/ countries. It is very important to have Safety Data Exchange Agreements in place defining the process for exchange of safety information, including timelines and regulatory reporting responsibilities. Processes should be in place to avoid duplicate reporting. 4. Regulatory Authority Sources Individual serious unexpected adverse drug reaction reports originating from foreign regulatory authorities are subject to expedited reporting to other authorities by each MAH. Such reports usually need not be sent to originating regulatory authority unless otherwise stated. An individual case safety report (ICSR) is considered to be valid if it meets at least four minimum criteria, i.e., it has: (1) an identifiable reporter, (2) an identifiable patient, (3) an adverse reaction, and (4) a suspect product. If one or more of these four criteria is missing, the case is not a valid AE report, i.e., reportable to a regulatory agency. However, if there is information regarding drug and adverse event, it needs to be databased, and the information may be used in assessment of risk-benefit balance and signal generation.
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CHAPTER 27 CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
All ADRs from clinical or epidemiological investigation, spontaneous reports, and reports from regulatory agencies or literature that are both serious and unexpected are subject to expedited reporting [5,6]. The source of report (investigation, spontaneous, other) should always be specified. Causality assessment is required for clinical trial cases. All cases judged by either clinical investigator or sponsor as having a reasonable suspected causal relationship to the investigational product are subjected to expedite reporting. For purposes of safety reporting, adverse event reports associated with marketed products (spontaneous reports) are considered to have implied causality. Serious adverse events from clinical trials which are not related to study medication are not subjected to expedite reporting. Reports which are serious but expected are not usually required to be expedited. However, expected serious ADRs showing significant increase in frequency will require to be processed on an expedite basis. Lack of efficacy for life-threatening disease, vaccines, or contraceptives are considered as expedited reports. Reports of overdose, dosing error with no adverse event outcome need not be reported as adverse reactions. In a blinded clinical study, when a serious adverse reaction is judged reportable on an expedited basis, it is recommended that the blind be broken only for that specific patient by the sponsor even if the investigator has not broken the blind. It is also recommended that the blind be maintained for those personnel involved in analysis and preparation of clinical trial reports. The blind can be broken independently by the pharmacovigilance team involved in processing and reporting of adverse events for MAH to the regulatory agencies. However, when a fatal or other serious outcome is the primary efficacy endpoint in a clinical investigation, the integrity of the clinical investigation may be compromised if the blind is broken. Under these circumstances, it may be appropriate to reach agreement with regulatory authorities in advance regarding serious events that would be treated as disease-related and not subject to routine expedited reporting. Serious adverse events associated with an active comparator should be reported by sponsor to the manufacturer of the active control or to appropriate regulatory agencies. Adverse events associated with placebo will usually not satisfy the criteria for an ADR and, therefore, for expedited reporting. For poststudy events, a causality and expectedness assessment is needed for a decision on whether or not expedited reporting is required. All information related to SAEs should be shared with other Investigators and Ethics Committees and Institutional Review Boards as per ICH GCP Guidelines. In addition to ICSRs, any safety information that could change the risk-benefit evaluation for the product should be communicated to regulatory authorities such as safety findings from an in vitro animal or epidemiological, preclinical, or clinical study that suggests a significant human risk, such as evidence of mutagenicity, teratogenicity, carcinogenicity, or lack of efficacy with a drug used in a life-threatening or other serious disease. Fatal or life-threatening, unexpected ADRs from clinical trials need to be reported to regulatory agencies no later than 7 calendar days from the day of knowledge by the sponsor followed by complete report with assessment within additional 8 calendar days. Other serious, unexpected ADRs need to be reported within 15 calendar days after first knowledge by sponsor/company. When additional medically relevant information is received for a previously reported case (called initial case), the reporting time clock is considered to begin again for submission of the follow-up report. In addition, a case initially classified as a nonexpedited report would qualify for expedited reporting
CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
411
upon receipt of follow-up information that suggests that the case should be re-classified from nonserious to serious. Cases of nonserious ADRs need not be reported on an expedited basis. These nonserious ADRs are included in periodic safety update reports. However, in the European Union and some African and Latin American countries these are reported within 90 calendar days. The following elements need to be considered while processing ICSRs: 1. Assessing Patient and Reporter Identifiability Patient and reporter identifiability is important in order to avoid case duplication and facilitate follow-up of appropriate cases. One or more of the following should automatically qualify a patient as identifiable: age (or age category, e.g., adolescent, adult, elderly), gender, initials, date of birth, name, patient identification number. Further, a case should have minimum four criteria for case reporting. 2. The Role of Narratives The objective of the narrative should be to summarize all relevant clinical and related information in a logical sequence. Normally it should be presented in the chronology of patient experience. The narrative should summarize all relevant clinical and related information, including patient demography, medical and concomitant disease history, concomitant and other treatment details, investigations performed, clinical course of disease, diagnosis and ADRs with their outcome. Any relevant autopsy or postmortem findings—if any—should be included in the narrative summary. In follow-up reports, new information should be clearly identified. 3. Clinical Case Evaluation The report should include the verbatim term as used by the reporter or an accurate translation of it. Additional information should be sought from HCP, if required. 4. Follow-up Information Follow-up information should be sought for incomplete cases and the priority should be as follows: (1) serious and unexpected, (2) serious and expected, and (3) nonserious and unexpected. Follow-up information can be obtained via a telephone call and/or site visit and/or written request preferably using a targeted questionnaire. For serious ADRs, it is important to continue follow-up and report new information until the outcome has been established or the condition is stabilized. The duration for follow up of such cases is a matter of judgment. 5. Pregnancy Exposure All cases of pregnancy exposure received from HCPs or consumers where the embryo/fetus could have been exposed to one of its medicinal products, should be appropriately followed up. Patient may become pregnant either during the treatment or after the completion of treatment with a medicinal product, and then all such cases of exposed pregnancy shall be monitored for an adverse outcome or adverse drug reaction in the mother, fetus, infant, or child. Reports of pregnancy exposure are considered serious if they are associated with serious ADRs and/or with abnormal pregnancy outcome. All pregnancy exposure cases reported spontaneously shall be followed up to obtain pregnancy exposure outcome. Reports of induced termination of pregnancy without information on congenital malformation, reports of pregnancy exposure without outcome data, or reports which have a normal outcome, are not required to be reported as individual case reports since there is no adverse drug reaction. These reports form part of periodic safety update reports. However, all cases of use of a medicinal product during
412
CHAPTER 27 CLINICAL AND POST APPROVAL SAFETY DATA MANAGEMENT
pregnancy are required to be submitted as individual case reports on expedited basis if there is a risk management program for one or more products to which the embryo/fetus has been exposed. The CIOMS-I form has been widely accepted standard for expedited adverse event reporting. Med Watch is used for reporting to US FDA, if E2B submission through electronic gateway runs into any trouble or is not possible. The Medical Dictionary for Regulatory Activities (MedDRA) should be used for coding adverse events. WHO DDE should be used for coding noncompany products and ICH E2B/M2 guidelines should be followed for electronic reporting of ICSRs.
REFERENCES [1] ICH E 2A: Clinical Safety data Management Definitions and Standards for Expedited Reporting (CPMP/ ICH/377/95), June 1995, European Medicines Agency. [2] ICH E2D: Post Approval Safety Data Management Note for Guidance on Definitions and Standards for expedited Reporting (CPMP/ICH/3945/03), November 1993, European Medicines Agency. [3] The Uppsala monitoring system, WHO collaborating Centre for International Drug Monitoring World Health Organization; 2002, pp. 28 34. [4] World Health organization. Safety of medicines. A guide to detecting and reporting adverse drug reactions why health professionals need to take action. Geneva: World Health Organization; 2002. [5] Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines, Food and Drug Administration, March 2001 (draft). ,http://www.fda.gov/cder/ guidance/4153dft.pdf.. [6] Safety Reporting Requirements for Human Drug and Biological Products, Proposed Rule, Food and drug Administration, March 2003. [7] ,http://www.ema.europa.eu..